Inflammation is defined as the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue. Inflammation may be acute (early phase of response) or chronic (occurs over a long time). Acute inflammation involves polymorphonuclear neutrophil leukocytes while chronic inflammation involves monocytes, macrophages, lymphocytes and plasma cells (collectively, mononuclear leukocytes). One affect of both acute and chronic inflammation is the sensation of pain which can be either neuropathic or nociceptive. Some common ailments associated with neuropathic pain are lower back pain, neuralgia/fibromyalgia, diabetic neuropathic pain and pain associated with multiple sclerosis. Common ailments associated with nociceptive pain are arthritic pain, particularly osteoarthritis and rheumatoid arthritis, post-operative pain, cancer-related pain and HIV-related pain.
Matrix metalloproteinases (MMPs) are a family of structurally related zinc-containing enzymes that have been reported to mediate the breakdown of connective tissue in normal physiological processes such as embryonic development, reproduction, and tissue remodelling. Over-expression of MMPs or an imbalance between MMPs has been suggested as factors in inflammatory, malignant and degenerative disease processes characterized by the breakdown of extracellular matrix or connective tissues. MMPs are, therefore, targets for therapeutic inhibitors in several inflammatory, malignant and degenerative diseases such as rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis, multiple sclerosis, gingivitis, corneal epidermal and gastric ulceration, atherosclerosis, neointimal proliferation (which leads to restenosis and ischemic heart failure) and tumor metastasis. MMP-2 (72 kDa gelatinase/GelatinaseA) degrades the extracelluar matrix components of the basement membrane. Their substrates include types IV and V collagen, fibronectin, elastin, and denatured interstitial collagens. Matrix degradation attributed to this proteinase has been shown to play an important role in the progression of such diseases as atherosclerosis, inflammation, stroke, and tumor growth and metastasis. However there has not been much literature demonstrating the use of MMP inhibitors and specifically inhibitors to MMP-2 to treat pain. For example, Yamamoto and coworkers (Neuroscience Letters, 347(2), (2003), 77-80) showed that injecting MMP-2 intrathecally in the rat formalin test (a model of inflammatory pain) depressed the Phase I agitation behavior but not the phase II behavior and that this analgesic affect was antagonized by the broad spectrum, hydroxamic acid containing, MMP inhibitor ONO-4817 (Ki values are 0.45, 0.73, 1.1, 1.1, 2.1, 42 and 2500 nM for MMP-12, MMP-2, MMP-8, MMP-13, MMP-9, MMP-3 and MMP-7 respectively). When the MMP inhibitor ONO-4817 was given alone it had no affect on the rat formalin test.
Recently, Ji and coworkers (Nature Medicine 14 (13), (2008), 331-336) have found that certain matrix metalloproteinases (MMPs) were upregulated during the early stages of injury via a spinal nerve ligation animal model. Specifically, they found that MMP-9 was upregulated in injured dorsal root ganglion (DRG) primary sensory neurons in the early phase of the L5 spinal nerve ligation (SNL) neuropathic pain model (first day and then declining after 3rd day) and that MMP-2 had a delayed response in the model (upregulation starting from day 7 and still present on day 21). They also found that MMP-2 induces neuropathic pain by IL-1β cleavage and astocytic extracellular signal-regulated kinase (ERK) activation. They also found that endogenous matrix metalloproteinase inhibitors (TIMP-1 and TIMP-2) also suppressed neuropathic pain in the model. Kobayashi and coworkers (Molecular and Cellular Neuroscience, 39, (2008), 619-627) also recently demonstrated that MMPs degrade peripheral myelin basic protein (MBP) and that a broad spectrum, hydroxamic acid containing MMP inhibitor (GM6001) was found to attenuate mechanical nociception.
Matrix metalloproteinase have been tested clinically in a few indications. Most predominantly in arthritis and cancer. Inhibitors that have entered clinical trials for an oncologic indication include prinomastat (AG3340; Agouron/Pfizer), BAY 12-9566 (Bayer Corp.), batimistat (BB-94; British Biotech, Ltd,), BMS-275291 (formerly D2163; Celltech/Bristol-Myers Squibb), marimastat (BB 2516; British Biotech, Ltd./Schering-Plough) and MMI270(B) (formerly CGS-27023A; Novartis). Many of the hydroxamic acid containing MMP inhibitors exhibit very broad toxicities in humans. For example, Marimastat, which contains a hydroxamate moiety, exhibited time-dependent and dose-dependent musculoskeletal toxicities (arthralgia, myalgia, tendinitis) in humans. Other toxicities for marimastat include ascites, disseminated carcinoma, chills, cholangitis, dizziness, dyspnea, edema, fatigue, fever, gastrointestinal (anorexia, nausea, vomiting, diarrhea, constipation), gastrointestinal hemorrhage, headache, heartburn, hepatic toxicity, hypercalcemia, hyperglycemia, rash, and shortness of breath. It is not known whether the toxicities exhibited by many of the MMP inhibitors are attributed to the hydroxamic acid moiety, however, it is clear that having an MMP inhibitor that does not contain a hydroxamic acid group could reduce many potential metabolic liabilities. One of the few non-hydroxamic acid containing compounds that have been tested in humans exclusively for the treatment of cancer is the tryptophan based acid S-3304 ((R)-3-(1H-Indol-3-yl)-2-(5-p-tolylethynyl-thiophene-2-sulfonylamino)-propionic acid) and which no evidence of musculoskeletal toxicities has been observed in animals or man. However, S-3304 has been found to give such adverse events in humans as headaches, somnolence, vomiting, nausea and gastrointestinal pain (van Marie, S. et al. Int. J. Clin. Pharmacol. Ther 2005; 43: 282-293). Further analysis of this compound in human blood found the formation of several hydroxylated metabolites (Chiapppori, A. A. et al. Clin. Cancer Res. 2007, 13(7), 2091-2099). Two of the main metabolites involved hydroxylation around the indole ring of the tryptophan moiety. Another metabolite involved hydroxylation of the toluene methyl portion of the molecule. It is clear that reducing the rate of such metabolically induced hydroxylations could reduce the metabolic liabilities of S3304 and/or enhance the overall bioavailability of the compound and possibly lead to an enhancement to the target tissue's exposure.
Kushner and coworkers (Kushner, D. J.; Baker, A.; Dunstall, T. G. Can J. Physiol Pharmacol, 77(2), (1999) p. 79-88) have presented examples of how incorporating deuterium into a drug can often reduce the level of metabolic induced transformations especially those mediated by Cytochrome P450. This reduce rate of Cytochrome P450 induce metabolism can sometimes translate directly to enhanced bioavailability. The reason for this is due to the fact that atomic substitution of a hydrogen by a deuterium in a drug alters the strength of the carbon-deuterium bond of the drug, while keeping it's 3D surface very similar to that of the nondeuterated version. Substitution of deuterium for hydrogen, can give rise to an isotope effect that can alter the pharmacokinetics of the drug. In a reaction in which the cleavage of a C—H bond is rate determining the same reaction of the C-D analogue will be reduced. For example Schneider and coworkers (Scheneider, F.; et al., BIRDS Pharma GmbH, Arzneimittel Forschung (2006), 56(4), p. 295-300) have shown that replacing several of the hydrogen atoms around one of the aromatic rings of the COX-2 inhibitor Refecoxib (4-(4-methylsulfonylphenyl)-3-phenyl-5H-furan-2-one) with deuterium (at positions 2′,3′,4′,5′ an 6′) enhanced the oral bioavailability of the drug without affecting it's COX-2 selectivity. If one applied this strategy to the tryptophan based acid S-3304 one could reduce its susceptibility to cytochrome P-450 hydroxylation and ultimately enhance its overall bioavailability and possibly it's target tissue compound concentration.
Another possible affect of incorporating deuterium into a drug is on its polymorphic (i.e., different crystalline forms) properties. For example, Hirota and Urushibara (Bulletin of the Chemical Society of Japan, 32(7), (1959), 703-706) have shown that replacing a single vinylic hydrogen for deuterium on Allocinnamic acid can change both the melting point and the intensity of the x-ray diffraction pattern of the molecule. Lin and Guillory (Journal of Pharmaceutical Science, Vol. 59(7), (2006), 972-979) have shown that sulfanilamide-d4 exhibited smaller heats of transition and heats of fusion for its various crystalline states as compared to it's corresponding non-deuterated forms. Finally, Crawford and co-workers (Crawford, S. et al., Angewandte Chemie International Edition, 48(4), (2009), 755-757) recently showed that the crystalline form of fully deuterated pyridine adopts a unique configuration that can only be obtained under high pressure with the non-deuterated parent. Their work clearly showed that replacing hydrogen for deuterium changes the strength of interaction between various atoms in neighboring molecules causing a change in the crystalline arrangement to one that is more energetically favorable. This change in crystalline arrangement or polymorph may allow for improved dissolution properties and enhanced bioavailability.
A series of MMP inhibiting compounds containing a phenylethynyl-thiophene functional group and having no hydroxamic acid functionality is disclosed. Additionally, the invention relates to the present compounds and a method for treating pain in a patient.